xevinapant (Debio 1143) / Debiopharm, Ascenta, Ascentage Pharma, EMD Serono - LARVOL DELTA

Adjuvant Palbociclib for ER+ Breast Cancer in the PALLAS Trial (ABCSG-42/AFT-05/PrE0109/BIG-14-13): Post-Recurrence Treatment and Overall Survival (SABCS 2025) - " 5,796 pts enrolled at 406 centers in 21 countries worldwide over 3 y. In the intent-to-treat (ITT) population, with a median follow-up of 82.7 months (mo), 7-y outcomes for iDFS, DRFS and OS are shown in the table. The PALLAS trial revealed significant differences in treatment post-DR that impact OS. Reduced/delayed use of metastatic CDK4/6i after adjuvant P was associated with significantly poorer OS, suggesting that patients who relapse after adjuvant CDK4/6i may still benefit from metastatic CDK4/6i. This has implications for optimal treatment in those who relapse after adjuvant CDK4/6i and warrants further study to determine if this is therapy-specific or an overarching biological effect."

Clinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Negative Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • HER-2

Xevinapant or Placebo Plus Platinum-Based Chemoradiotherapy in Unresected Locally Advanced Squamous Cell Carcinoma of the Head and Neck (TrilynX): A Randomized, Phase III Study. (PubMed, J Clin Oncol) - "Xevinapant plus CRT did not improve EFS (EFS was shorter with xevinapant v placebo) and demonstrated an unfavorable safety profile versus placebo plus CRT in patients with unresected LA SCCHN."

Clinical • Journal • P3 data • Head and Neck Cancer • Hematological Disorders • Neutropenia • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

The cytotoxic effect of DEBIO 1143 on triple-negative murine breast cancer cell lines: Insights from in vitro and in silico studies. (PubMed, Tissue Cell) - "DEBIO 1143 was associated with reduced apoptotic cell death and increased necroptosis-like and autophagy-associated responses in TNBC cells. These findings support its development as a multimodal therapeutic strategy for aggressive breast cancer subtypes."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • ANXA5 • BECN1 • HER-2

RAVINA: Radiotherapy Plus Xevinapant in Older Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma (clinicaltrials.gov) - P2 | N=13 | Terminated | Sponsor: European Organisation for Research and Treatment of Cancer - EORTC | N=230 ➔ 13 | Suspended ➔ Terminated; discontinuation of all ongoing studies involving xevinapant

Enrollment change • Trial termination • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

A Study of Xevinapant With Cisplatin and Radiation Therapy After Surgery in People With Head and Neck Cancer (clinicaltrials.gov) - P2 | N=4 | Completed | Sponsor: Memorial Sloan Kettering Cancer Center | Active, not recruiting ➔ Completed

Trial completion • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma of Head and Neck

"SMAC"-down for the apoptosis-restoring drug, Xevinapant: What does its story reveal? (PubMed, Clin Cancer Res) - "High intratumoral drug exposure was confirmed, but supporting pharmacodynamic data were largely derived from indirect pro-apoptotic signals in peripheral blood biomarkers. Here, we review xevinapant's trajectory, highlighting both the promise and risks of apoptosis-directed therapies, and extract key lessons for future oncology drug development by examining existing preclinical evidence, pharmacodynamic biomarkers, trial design and interpretation, and challenges associated with dosing agents that have a narrow therapeutic index."

Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • TNFA

Green synthesis of silver nanoparticles under ambient conditions using onion, turmeric, and galangal extracts with antibacterial activity against E. coli and S. aureus. (PubMed, Biotechnol Rep (Amst)) - "UV-Vis spectra confirmed nanoparticle synthesis with surface plasmon resonance peaks at 406-425 nm...All samples showed MIC/MBC of 50 µg/mL against S. aureus, whereas onion-derived AgNPs were most effective against E. coli (MIC 200; MBC 400 µg/mL). These plant extracts are promising low-cost bioresources for green nanomaterial production."

Journal

Xevinapant, a SMAC Mimetic, depletes the HIV-1 reservoir and delays viral rebound in vivo without reversing HIV-1 latency (AIDS 2026) - "Our results show that Xevinapant can deplete the HIV-1 reservoir in vivo . Unlike some other SMAC Mimetics, Xevinapant did not reverse HIV-1 latency in HIS mice. Taken together, our results demonstrate the depletion of the HIV-1 reservoir in vivo by a SMAC Mimetic independent of latency reversal, suggesting that exploiting the extrinsic apoptosis pathway offers a new direction towards an HIV-1 cure."

Preclinical • Human Immunodeficiency Virus • Infectious Disease • CD34 • IL2RA

The SMAC-mimetic xevinapant differentially enhances cisplatin and immune checkpoint blockade efficacy in high-risk HPV-positive tumors. (PubMed, Transl Oncol) - "These findings identify a biologically defined vulnerability of HPV-positive HNSCC to IAP blockade and support xevinapant as an apoptosis-sensitizing and immunomodulatory agent rather than a uniform therapeutic intensifier."

Checkpoint inhibition • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Organic-inorganic hybrid materials with high phase transition temperatures regulated by halogen substitution. (PubMed, Dalton Trans) - "All exhibit reversible solid-solid phase transitions at 406 K, 419 K, and 422 K, respectively, and semiconducting behavior with tunable band gaps of 3.298-4.398 eV. Supercell and Hirshfeld surface analyses reveal that progressive halogen substitution (I → Br → Cl) strengthens C-H⋯X hydrogen bonds, increases lattice confinement, and raises the rotational potential of organic cations, providing a structural basis for high-temperature phase transitions. This work demonstrates that halogen modulation in the inorganic framework is an effective strategy for designing multifunctional organic-inorganic hybrid materials with controllable thermal and optoelectronic properties."

Journal

Poor radiation sensitivity and potential radiosensitizers for betel-nuts related head and neck squamous cell carcinoma in Taiwan (AACR 2024) - "Purpose & Polo-like kinase 1 inhibitor(volasertib), gluconate(blocking citrate transport & glucose metabolism), IAP inhibitor(Debio1143), glutaminase 1 inhibitor(CB839) were tested on TW2.6 to evaluate synergistic effects with radiation. In Taiwan, patients with R/M HNSCC progressing within 3 months after CCRT could be rescued by early ICIs. Recently, sequential CCRT followed by ICI or Debio-1143 with CCRT showed potential survival benefits. In our studies, novel agents such as PLK inhibitor, gluconate, and CB839 had even better radiosensitization compared with Debio1143."

IO biomarker • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ARID1B • ATM • BCL2 • CCND3 • CDK1 • CDK12 • DDR2 • EPHB1 • FAT1 • FGF10 • FLCN • HRAS • MITF • PDGFRB • PD-L1 • PIK3CA • PLK1 • RICTOR • SDHA • SOX9 • STK11 • TERT • TMB • TNFAIP3 • TP53

Radio-sensitizing activity in apoptosis pathway in HPV+ and HPV- head and neck squamous cell carcinoma (HNSCC) (AACR 2025) - "This study evaluates the efficacy of the IAP inhibitor AT406, alone and with radiation, in both HPV positive (UM-SCC47 and UD-SCC2) and HPV-negative (Cal27 and DET562) HNSCC cell lines...In addition, Liquid Chromatography- Mass Spectrometry (LC-MS/MS) is being utilized to profile changes in protein expression under different treatment conditions to identify molecular contributors to resistance mechanisms. These studies aim to provide mechanistic insights into IAP inhibition and inform the development of combination therapies outcomes in HNSCC."

Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • BIRC3 • CASP3 • CASP7 • XIAP

A phase 1 study of the IAP inhibitor xevinapant (Debio 1143) to evaluate food effect and drug-drug interactions with a proton pump inhibitor in healthy volunteers (AACR 2024) - P1/2, P3 | "These data indicate that xevinapant can be administered without regard to food or gastric acid reducing agents, which would be advantageous for patient convenience and compliance."

Clinical • P1 data • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Extended treatment with IAP inhibitor xevinapant post radiotherapy improves therapeutic efficacy and promotes antitumor immunity in preclinical models (AACR 2024) - "Extended dosing of xevinapant post concurrent RT improved antitumor efficacy and prolonged survival of tumor-bearing mice. Mechanistic investigation suggested that such benefit may be, in part, modulated by xevinapant enhanced antitumor immunity."

Preclinical • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • CAFs • CSF2 • CXCL10

EXtRaCT study: Study of Xevinapant With Radiation and Chemotherapy for Patients With Head and Neck Cancer (clinicaltrials.gov) - P1 | N=42 | Terminated | Sponsor: University of Chicago | Trial completion date: Oct 2027 ➔ May 2025 | Active, not recruiting ➔ Terminated | Trial primary completion date: Oct 2027 ➔ May 2025; Drug no longer being developed by manufacturer

Trial completion date • Trial primary completion date • Trial termination • Head and Neck Cancer • Oncology • Oropharyngeal Cancer • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

Discontinuation of the double-blind, placebo-controlled randomized, phase III GORTEC 2022-01 trial of radiotherapy-cetuximab and xevinapant in patients with locally advanced squamous cell carcinoma of the head and neck, unfit for cisplatin. (PubMed, Radiother Oncol) - "XXL was a placebo-controlled phase 3 evaluating cetuximab-radiotherapy and xevinapant (IAP inhibitor) in locally advanced squamous cell carcinoma of the head and neck, ineligible for cisplatin (Unfit). Following the unfavorable outcomes of Trilynx [1], XXL the trial was prematurely discontinued after the enrollment of 19 patients and subsequently unblinded; the safety analysis then revealed an increase in treatment-related deaths with xevinapant."

Journal • P3 data • Head and Neck Cancer • Oncology • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck

The smac mimetic Xevinapant increases the efficacy of radiotherapy in triple negative breast cancer but only in the presence of tumor necrosis factor alpha (AACR 2026) - "Xevinapant (AT406) synergizes with RT in the presence of TNFα to induce the death of triple-negative breast cancer cells. TNFα is central to this radiosensitization through activation of the programmed cell death. These results are promising, and investigations are underway to characterize a potential TNFα gene signature that could be used to identify patients that could respond to such a combination therapy."

Clinical • Breast Cancer • Estrogen Receptor Positive Breast Cancer • HER2 Breast Cancer • HER2 Positive Breast Cancer • Hormone Receptor Breast Cancer • Oncology • Solid Tumor • Triple Negative Breast Cancer • CASP3 • CASP7 • ER • HER-2 • TNFA

SOX9-ICASPASE9 MOUSE MODEL WOULD BE ABLE TO GENERATE CHIMERIC KIDNEY (ISN-WCN 2026) - "Adding AP20187 (100 nM) and AT406 (50 μM) made those Sox9-positive cells eliminate...When donor's UPCs connect to recipient's UPCs and ureter, urine produced by donor kidney cells can excreted via the recipient's ureter. We are trying to make chimeric kidneys with this system."

Preclinical • Infectious Disease • HOXB7 • SOX9

Absolute Bioavailability and Absorption, Distribution, Metabolism, and Excretion of [14C]Xevinapant, a Potent, Oral, Small-Molecule IAP Inhibitor. (PubMed, Clin Pharmacol Drug Dev) - "The absolute oral bioavailability of xevinapant was determined to be 57.8%. The clearance of [14C]xevinapant was 12.2 L/h and the volume of distribution at steady-state was 75.3 L. Xevinapant was well tolerated in healthy male subjects, with no clinically significant findings in clinical laboratory evaluations, vital signs, ECG, or physical examinations."

Journal

Comparing and combining xevinapant with ATR and PARP inhibition for the radiosensitization of HPV-negative HNSCC cells. (PubMed, Sci Rep) - "Both tuvusertib and olaparib induced stronger radiosensitization than xevinapant and combining both agents resulted in especially profound radiosensitization in three out of the four cell lines tested, whereas their combination with xevinapant or the combination of xevinapant with cisplatin was less effective. Assessment of cell death induction via annexin V/DAPI staining failed to generally predict cytotoxicity or radiosensitization of these approaches. Overall, our data are in line with the recent failure of the phase 3 TrilynX trial and suggest further investigation of ATR and PARP inhibition for the curative treatment of HPV-negative HNSCC."

Clinical • Journal • Head and Neck Cancer • Oncology • Solid Tumor • Squamous Cell Carcinoma • Squamous Cell Carcinoma of Head and Neck • ANXA5

Identification, structural elucidation and nonclinical characterization of oxMET1: A further major metabolite of xevinapant? (PubMed, Xenobiotica) - "Based on these findings, this metabolite did not raise safety concerns according to the MIST guidelines, however it warrants further characterization of its drug-drug interaction (DDI) potential according to current DDI guidelines. The integrated workflow presented here highlights the importance of metabolite characterization in drug development."

Journal • Oncology

IAP Antagonists Selectively Eliminate Therapy-Induced Senescent Cancer Cells via TNFα-Independent Apoptosis. (PubMed, Cancer Sci) - "Here, we show that AZD5582 and AT406, potent antagonists of cellular inhibitor of apoptosis proteins 1 and 2 (cIAP1 and cIAP2) and X-linked inhibitor of apoptosis protein (XIAP), selectively eliminated HCT116 and RKO cells that had undergone senescence following treatment with a chemotherapeutic agent such as trifluridine, camptothecin, or doxorubicin. At physiological concentrations, TNFα sensitized non-senescent, proliferating cancer cells, but not TIS and nutlin-3a-induced senescent cancer cells, to apoptosis in the presence of IAP antagonists. Collectively, these findings suggest that IAP antagonists could serve as effective concomitant agents to TIS-inducing chemotherapy that promotes TNFα secretion within tumors, functioning not only as TNFα-independent senolytics but also as potentiators of TNFα-mediated apoptosis in adjacent non-senescent, proliferating cancer cells."

Journal • Oncology • BIRC3 • CASP8 • TNFA • XIAP

Ex Vivo Drug Efficacy in High-Risk Paediatric Cancers: A Comprehensive Analysis of the ZERO Cohort (LCC 2026) - "Notably, brain tumour samples demonstrated differential sensitivity to Mitogen-Activated Protein Kinase signalling pathway (MAPK) inhibitors with strong correlations observed with the JAK/STAT pathway inhibitor ruxolitinib and with xevinapant, a SMAC mimetic that targets anti-apoptotic signalling proteins (XIAP, cIAP1/2). Conclusion Our HTS pipeline revealed tumour-type specific sensitivities and novel drug-drug correlations, which may guide future combination efficacy testing and serve as predictive markers for potential drug responses. Further evaluation of the improved ZERO program will uncover additional drug correlations, paving the way for innovative therapies in paediatric cancer"

Preclinical • Brain Cancer • Neuroblastoma • Oncology • Pediatrics • Sarcoma • Solid Tumor • XIAP

SMAC Mimetic Targets Glioblastoma Stem Cells and Reprograms the Associated Tumor Microenvironment (SNO 2025) - "Taken together, our findings highlight the dual mechanism of action of Xevinapant in targeting both tumor-intrinsic and microenvironmental resistance mechanisms. These results support the continued clinical development of Xevinapant and provide a strong rationale for combination strategies aimed at improving treatment efficacy in GBM."

Biomarker • Tumor microenvironment • Brain Cancer • Glioblastoma • Oncology • Solid Tumor

SMAC Mimetic Targets Glioblastoma Stem Cells and Reprograms the Associated Tumor Microenvironment (WFNOS 2025) - P | "Taken together, our findings highlight the dual mechanism of action of Xevinapant in targeting both tumor-intrinsic and microenvironmental resistance mechanisms. These results support the continued clinical development of Xevinapant and provide a strong rationale for combination strategies aimed at improving treatment efficacy in GBM."

Biomarker • Tumor microenvironment • Brain Cancer • Glioblastoma • Solid Tumor